17-61716043-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_032043.3(BRIP1):c.2400C>G(p.Tyr800Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000256 in 1,601,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y800Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 1.07

Variant links:

Genes affected

BRIP1 (HGNC:20473): (BRCA1 interacting helicase 1) The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations. [provided by RefSeq, Jul 2008]

BRIP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 17-61716043-G-C is Pathogenic according to our data. Variant chr17-61716043-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61716043-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.2400C>G	p.Tyr800Ter	stop_gained	17/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.2400C>G	p.Tyr800Ter	stop_gained	17/20	1	NM_032043.3	P2	Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

248886

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134612

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000532

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000276

AC:

AN:

1449556

Hom.:

Cov.:

AF XY:

0.0000208

AC XY:

AN XY:

720452

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000362

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152034

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000308

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 07, 2023	This variant changes 1 nucleotide in exon 17 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 10 individuals affected with breast and ovarian cancer (PMID: 26315354, 29368626, 29958926, 32359370) and peritoneal cancer (PMID: 26720728) and in one individual age 70 years or older without cancer in the FLOSSIES database. This variant has been detected in a breast cancer case-control meta-analysis in 7/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRIP1_000008). This variant has also been reported in the compound heterozygous state with a second BRIP1 mutation in an individual affected with Fanconi anemia (PMID: 16116424). This variant has been identified in 6/248886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 01, 2022	The p.Y800* pathogenic mutation (also known as c.2400C>G), located in coding exon 16 of the BRIP1 gene, results from a C to G substitution at nucleotide position 2400. This changes the amino acid from a tyrosine to a stop codon within coding exon 16. This mutation was reported in conjunction with a second truncating mutation in a Fanconi anemia type J (FA-J) patient (Levran O et al. Nat. Genet. 2005 Sep;37:931-3). This mutation has also been reported in individuals with a personal and/or family history of ovarian and/or breast cancer (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107; Norquist BM et al. JAMA Oncol. 2016 Apr;2:482-90; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Meiss AE et al. Hum Pathol, 2018 12;82:20-31; Arvai KJ et al. Hered Cancer Clin Pract, 2019 Jul;17:19; Dorling et al. N Engl J Med. 2021 02;384:428-439). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 22, 2021	- -

Fanconi anemia complementation group J

Pathogenic:2

Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 07, 2011	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 16, 2021	Variant summary: BRIP1 c.2400C>G (p.Tyr800X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.8e-05 in 360186 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in BRIP1 causing Fanconi Anemia Complementation Group J (2.8e-05 vs 0.0004), allowing no conclusion about variant significance. In addition, this variant has also been reported in 1 / 7325 European American woman who was older than age 70, and cancer free (in the FLOSSIES database). The variant, c.2400C>G, has been reported in the literature in a compound heterozygous individual affected with Fanconi Anemia Complementation Group J (FANCJ), who carried a pathogenic BRIP1 variant in trans (Levran_2005). In addition, the variant was also reported in heterozygous state in several individuals affected with ovarian cancer, breast cancer and other tumor phenotypes (e.g. Norquist_2016, Ramus_2015, Weber-Lassalle_2018, Susswein_2016). A recent large case-control study evaluating breast cancer (BrC) cases and controls in the Breast Cancer Association Consortium (BCAC), reported no risk association with familial breast cancer for BRIP1 truncating variants (Dorling_2021). However, a recent meta-analysis found a moderate risk association for BRIP1 truncating variants (including the variant of interest) with ovarian cancer (overall odds ratio (OR) = 4.94, 95% CIs: 4.07-6.00, p <0.0001; Suszynska_2020). At least one publication reported lack of protein expression on immunoblot analysis in cells derived from a FANCJ patient, though the presence of a truncated protein couldn't be excluded, as the antibodies used bound the C terminus (Levran_2005). However, a truncating variant at this protein level (i.e. amino acid 800) is also expected to have a detrimental effect on protein function, as the BRCA1-BRIP1 interaction domain lies in residues 888-1063 (UniProt, PMID: 11301010). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Also known as c.2541C>G; This variant is associated with the following publications: (PMID: 26315354, 28152038, 29368626, 32295079, 29922827, 28888541, 26681312, 26720728, 23644138, 30322717, 31980526, 26689913, 29625052, 34308104, 35874679, 33804961, 33471991, 29958926, 32359370, 34887416, 31341520, 16116424) -

Familial cancer of breast

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 06, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 05, 2023	- -

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Mar 17, 2021

PS4, PVS1 -

Breast and/or ovarian cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

Familial cancer of breast;C1836860:Fanconi anemia complementation group J

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change creates a premature translational stop signal (p.Tyr800*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is present in population databases (rs574552037, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with ovarian cancer and Fanconi anemia type J (PMID: 16116424, 26315354). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 2541C>G. ClinVar contains an entry for this variant (Variation ID: 142343). For these reasons, this variant has been classified as Pathogenic. -

Ovarian cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

BRCAlab, Lund University

Aug 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.57

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Benign

0.15

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.91

MutationTaster

Benign

1.0

A;A

Vest4

0.91

GERP RS

-3.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over